Publication Date

5-2018

Advisor(s)

Gloster Aaron

Department

Neuroscience & Behavior

Abstract

Over 65 million individuals around the globe currently suffer from epilepsy, and nearly one third of those individuals are unable to achieve seizure freedom from antiepileptic drugs. Unfortunately, much remains unknown about the mechanisms underlying epileptogenesis. By understanding how seizures are able to propagate and achieve cortex-wide synchronization, we offer those suffering from retractable epilepsy a hope for reaching seizure freedom through better and more precise therapies. Inhibition is known to massively influence seizure properties, though sometimes in paradoxical ways. The research conducted in this paper was designed to elucidate the network properties of inhibition and inhibition’s role in altering epileptiform event (EE) characteristics. Our primary goals were to determine how EEs produced in environments with and without inhibition differed from one another, correlate inhibitory currents with EE production/propagation, and characterize general inhibitory trends as related to EE properties.

In order to achieve these goals, we developed an ex vivo slice model that allowed us to record from the anterior cingulate cortex with two extracellular electrodes (one in each hemisphere) and one intracellular electrode. Together, the extracellular and intracellular data allowed us to examine how EEs are generated and propagate, as well as measure the inhibitory dynamics as they occurred. We found that EEs produced in the BIC treatment (which lacked GABAergic inhibition) greatly differed from EEs produced in the 4AP treatment (which maintained GABAergic inhibition). 4AP produced a wider variety of EEs, indicating inhibition enabled increased EE complexity, duration, and areas. These differences were likely a result of the capacity for widespread synchronization made possible by inhibition. Importantly, however, inhibition reduced the rate of propagation, reduced the directionality, and increased the interhemispheric latency of the propagating EEs, indicating it was also acting as a preventative force against seizure spread. Using a spike-triggered average analysis, we discovered that inhibition was not only exerting distant feedforward inhibition across the corpus callosum to prevent EE propagation, but more importantly (and previously unknown), local feedforward inhibition within the same hemisphere as the generated EE was playing an even larger role in preventing EE propagation. Inhibition exerting effects within local circuits to prevent EE propagation had not previously been observed. This discovery offers the exciting possibility to control seizure spread between hemispheres with treatments localized exclusively to the ictal focus.

Share

COinS
 

© Copyright is owned by author of this document